Improving maternal child health among HIV-infected pregnant women and their children in Africa requires strategies that effectively address HIV and co-morbidities. Success of antiretroviral therapy is resulting in a growing population of HIV -exposed uninfected (HEU) children, still suffering poor outcomes. A high malaria burden among pregnant women and children, despite insecticide treated nets and trimethoprim-sulfamethoxazole (TS), contribute to these poor outcomes. Dihydroartemisinin-piperaquine (DP), an artemisinin combination therapy (ACT) with a long post treatment prophylactic effect, is highly effective and safe for malaria treatment in pregnant women and children but has not been evaluated for malaria prevention. We propose to test the hypothesis that enhanced malaria chemoprevention (DP +TS) vs. TS in pregnant women and their children during the first 2 years of life will reduce the incidence of malaria during the first 2 years of life. This hypothesis is based on observations that maternal and placental malaria increase the risk of infant malaria and that DP chemoprevention of HEU reduces malaria incidence. Additionally, we will evaluate the safety and pharmacokinetics of DP including interactions with efavirenz and examine malaria incidence in HEU after malaria chemoprevention discontinuation at 2 years of age. We plan to test our hypotheses in a double-blind, placebo-controlled, randomized trial of HIV-infected pregnant women in Tororo, Uganda, an area of high malaria transmission. The primary study endpoint is malaria incidence in children from birth to 24 months. Our 3 aims are: 1) To determine if enhanced (DP+TS) versus standard malaria chemoprevention (TS) during both pregnancy and infancy reduces malaria during the first 24 months of life. We will randomize 200 HIV-infected pregnant women to monthly DP+daily TS vs monthly placebo+daily TS during pregnancy. Infants will receive the same prevention regimen as their mother for 24 months. 2) To evaluate safety of monthly DP given for malaria prevention during pregnancy and early childhood. We will compare grade 3 and 4 toxicity and birth outcomes between the arms 3) To evaluate the pharmacokinetic exposure of concomitant DP and efavirenz during pregnancy. We will perform intensive PK for DP and EFV during the 3rd trimester and compare DP between HIV infected and uninfected pregnant women.